Renal manifestations of recreational drugs: A narrative review of the literature

Drug abuse has become a major problem of the modern world where drug-induced kidney injury can be caused by both prescribed drugs for clinical conditions and illegal (illicit) drugs or drugs of abuse. Heroin, cocaine, nicotine and alcohol are the most commonly abused drugs but with the emergence of various synthetic drugs, numerous novel descriptions of their nephrotoxic effects have been described. This review summarizes the key renal manifestations of recreational drugs as reported in case reports and case. A comprehensive review of published case reports and case series in English language of renal toxicity related to recreational drugs/drugs of abuse was conducted using search engines like PubMed/Medline. Publications which reported renal injury with raised creatinine levels, clinically symptomatic patients, those with oliguria and with renal biopsies are chosen. The medical literature on recreational drugs is full of claims of renal complications including different glomerular diseases, acute kidney injury, rhabdomyolysis, interstitial nephritis, and debilitating irreversible conditions like renal infarction and end stage renal disease, even though the pathogenesis of drug- related renal manifestations are not available for all the newer agents. The outcome of this review paper will help multidisciplinary physicians to understand the renal side effects of recreational drugs, their pathophysiology, and most importantly, the clinical presentations of renal dysfunction in relation each drug. Emphasizing these adverse effects will prevent future unfavorable outcomes.


Introduction
Substance abuse is common with a lifetime prevalence of 10% in the general American population, as stated in the National Survey on Drug Use and Health conducted by the Substance Abuse and Mental Health Service Administration (SAMHSA). [1] Generally, recreational drugs are divided into nine categories according to Drug Enforcement Administration: depressants, stimulants, hallucinogens, steroids, dissociative anesthetics, narcotic analgesics, inhalants, cannabis/ marijuana, and designer drugs. These drugs can have a direct or indirect effect on organ systems, of which the filtering units of the kidneys are the most affected. There is a wide range of side effects due to multiple mechanisms of injury the drugs can have-ranging from acute prerenal kidney injury (AKI) to severe functional and structural injuries. Rhabdomyolysis is the most common cause of AKI among users, due to immobilization and muscular breakdown of exertion. Vasoconstriction and ischemic renal injury are seen in cocaine and methamphetamine users. [2] Glomerular injury, such as minimal change disease, focal segmental glomerulosclerosis (FSGS) is seen in heroin and cocaine abusers. [3] Adulterants such as levamisole are known to cause anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. [4] This review discusses the nephrotoxic effects of stimulants, hallucinogens, steroids, dissociative anesthetics, narcotic analgesics, inhalants, and designer drugs, of which both the community and health care providers should become aware given their widespread use. The discussion on depressants, tobacco, e-cigarettes, alcohol, prescription opioid drugs is beyond the scope of this article.

Methods
A comprehensive search for published case reports and case series which reported renal injury in relation to the use of

Cocaine and crack cocaine
During the second millennium, with world trade being established from China to Europe and trade routes in India, came the cocaine that kept the trade market flourishing. Cocaine (benzoyl methylecgonine) was first introduced in the United States in 1854. It was extracted from the leaves of Erythorxylon coca. [86] 2.2.1. Incidence. In the United States, the number of people using cocaine increased by 57% from 2012 to 2017. Annual deaths increased by 200%, making cocaine the leading nonopioid cause of drug overdose death according to Centers for Disease Control and Prevention. [3]

Pathophysiology. A study by Fine et al in 2007 on
193 human immunodeficiency virus patients who underwent kidney biopsy, cocaine use was present in 16 (55%) of 29 with hypertensive renal changes compared with 6 (25%) of 24 without hypertensive renal changes. [4] A study by Paolo et al in a series of 40 autopsies, glomerular hyalinosis and periglomerular fibrosis was significantly higher in cocaine addicts along with a higher degree of arteriolar sclerosis, intimal and medial thickness and circumference. [87] The pathophysiological basis for cocainerelated renal injury is multifactorial [88] - (1) Has potent vasoconstrictive effects on vascular smooth muscle by a. Inhibiting catecholamine reuptake at the presynaptic nerve terminal b. Releasing norepinephrine and epinephrine from adrenal medulla c. Blocking norepinephrine reuptake in sympathetically innervated tissues d. Increased endothethelin-1 production resulting in decreased renal blood flow e. Involvement of renin-angiotensin-aldosterone system.
(2) Accelerated atherogenesis leading to renal infarction by increasing renal cellular oxidative stress and decreasing intracellular glutathione. It is also mediated by cocaineinduced stimulation of platelet aggregation and thromboxane synthesis. (3) Accelerated and malignant hypertension which hastens the progression of chronic kidney disease to end stage renal disease. (4) Formation of active metabolite cocaethylene which is highly toxic than cocaine alone leading to rhabdomyolysis. It could also be related to non-traumatic injury leading to acute skeletal myofibrillar degeneration and vasoconstriction leading to muscle ischemia and necrosis, or traumatic due to seizure or hyperthermia.

Clinical characteristics.
There are several case reports suggesting cocaine-induced rhabdomyolysis (Table 1). It has been associated with accelerated and malignant hypertension as well as hastening the progression of hypertensive nephrosclerosis to end stage renal disease. [48,89] Acute aortic thrombosis, renal artery thrombosis and dissection have been reported. [5,10] Other clinical charactertistics include acute interstitial nephritis, thrombotic microangiopathy and chronic kidney disease. Cocaine abuse in pregnancy can cause a decrease in fetal arterial flow, urine output, bladder cycle, higher resistance index of renal artery, thickening of the interlobular arterial wall of the fetal kidney and luminal narrowing. [90,91]

Cocaine with levamisole
Cocaine, in recent days, has been mixed with adulterants such as levamisole, dexamisole, and fentanyl. Levamisole, which is a discontinued anti-helminthic is the most common adulterant and when mixed with cocaine potentiates its effects.
2.3.1. Incidence. 69% of cocaine is adulterated with levamisole as reported by Drug Enforcement Administration. In an analysis of cocaine users in Seattle, Washington, approximately 80% of users who tested positive for cocaine also tested positive for levamisole. [92] 2.3.2. . Pathophysiology. A case series of 30 patients with ANCA-associated vasculitis in relation with cocaine and levamisole has been reported ( Table 1). The pathophysiology of levamisole-induced vasculitis involves [93] : 1. The action of catecholamines on neural synapses enhances the reuptake inhibition effect of cocaine. 2. Immunomodulation by promoting neutrophil mobility and chemotaxis, enhancing dendritic cell maturation, and promoting T cell proliferation that induces autoimmunity and vasculitis.

Clinical characteristics.
Cocaine with levamisole has immunomodulatory properties and causes crescentic pauciimmune GN, positive for both MPO and PR3 antibodies. Additionally, many patients also had antinuclear antibody positivity and low complements. A case report has shown an association of anti-glomerular basement membrane disease. [94]

Amphetamines
Amphetamines were first synthesized in 1887 and were used in the medical community to raise blood pressure and stimulate the central nervous system. During World War II, it was widely distributed among soldiers to combat fatigue and improve mood and endurance. [94] 2.4.1. Incidence. Among the illicit drugs, amphetamines remain a popular recreational drug in the world. According to SAMHSA, more than 150000 emergency department visits were decscribed from toxicity from amphetamines and its analogues. [
Rhidian et alm 2013. [72] Adebamiro et al, 2012. [73] Borek et al, 2012. [  In ancient Greece, a special form of mead (fermented honey) was used to induce vision known as mysteries. With this, came the cultivation of plants (peyote cactus, fly agaric and cannabis) containing entheogens (natural chemicals that induce hallucinations) throughout the world. [96] The percentage of people who were hallucinogen users in the past year increased from 0.8 percent (or 1.7 million people) in 2015 to 1.5 percent (or 3.1 million people) in 2019. [1] 2.6. LSD LSD (D-lysergic acid diethylamide) was first accidentally discovered in the labs by Dr Albert Hofmann in 1943. Eventually, U.S. military and CIA used it as a possible "truth drug" to induce prisoners to talk. Non-therapeutic use of LSD occurred in the late 1950s and 1960s.
2.6.1. Incidence. In a survey conducted in 2010 by National Survey on Drug Use and Health, 23 million US residents reported using LSD at least once. [97] 2.6.2. Pathophysiology. There are not a lot of research or studies on LSD but it has been noted that LSD-induced hyperthermia leads to rhabdomyolysis based on a case report by Berrens et al in 2010. [98] 2.6.3. Clinical characteristics. Patients can present with hypertension, tachycardia, agitation, seizures and AKI. There are also case reports of metabolic acidosis and rhabdomyolysis.

Magic mushrooms
Out of the 100,000 or more species of mushrooms worldwide, more than 100 are toxic. Identifying the specific species of mushrooms is important as there is a specific treatment for some mushrooms. Magic mushrooms (Psilocybe semilanceata) have become a popular form of substance abuse among young people. This fungus contains a hallucinogenic agent psilocybin, which resembles LSD. [33] Other mushroom intoxications include amatoxin syndrome and orellanine syndrome due to Cortinarius.

Incidence.
Magic mushroom is very popular in rave parties and college parties. Hallock et al based on a survey of 409 college students reported that 29.5% of responded experimented with psilocybin-containing hallucinogenic magic mushrooms. [33] Another study indicated that an estimated 21 million people in the US used magic mushrooms in the past. [68] 2.7.2. Pathophysiology.

Once ingested, psilocybin is dephosphorylated by alkaline
phosphatase to the active metabolite psilocin. 2. Both psilocybin and psilocin have affinity for serotonergic receptors, which are responsible for hallucinatory properties. 3. Mushrooms of the Cortinarius genus contain the toxin orellanine that causes inhibition of protein, RNA, and DNA synthesis. 4. It produces an orthosemiquinone radical that can lead to oxidative stress and direct toxicity if the renal tubular epithelium causes tubular necrosis, interstitial nephritis, and fibrosis.

Clinical characteristics.
Ingestion of magic mushrooms is regarded as having a low potential for arm. The most commonly reported adverse effects are anxiety, agitation, confusion, impaired concentration and judgment. Renal manifestations include renal failure from severe dehydration to nephritis and multiorgan failure.

MDMA
The first use of methamphetamine (injectable form of amphetamine) began in the 1960s. It is a drug which by increasing dopamine in the central nervous system, and causes dependence. Other street names are Speed, ice and crank. A pure form of 3,4-methylenedioxymethamphetamine, called "Molly" acts by enhancing the release of serotonin, dopamine and norepinephrine. Though it is a popular club drug as it produces euphoria, it is associated with serious side effects including rapid multiorgan failure, hyponatremia and rhabdomyolysis (Table 1).

Clinical characteristics.
Renal manifestations of MDMA (3.4-methylenedioxymethylamphetamine) (ecstasy) include rhabdomyolysis, malignant hypertension, hyponatremia, necrotizing vasculitis, thrombotic thrombocytopenic purpura and rapidly progressive glomerulonephritis. Gupta et al in 2018 published the first case report of crystal meth induced acute renal cortical necrosis, [86] in addition, to a myriad of cardiovascular and cerebrovascular complications like malignant hypertension, arrhythmias, aortic dissection, myocardial infarction, stroke, and cardiomyopathy. [93]

Dissociative anesthetics/ hallucinogens
Dissociative anesthetics include drugs like phencyclidine (PCP) (also belong to dissociative hallucinogen group), ketamine, and dextromethorphan that inhibit pain by dissociating the brain's perception of the pain.

PCP
PCP was first developed in the 1950s as a general anesthetic for surgeries. It was soon abandoned due to unwanted side effects, including psychosis and dysphoria. Due to its dissociative effects, it gained popularity as a drug of abuse. [100] Various case reports of PCP and rhabdomyolysis/acute renal failure since the 1970s are available in the literature (Table 1) cognitive defects, and psychosis. PCP blocks the uptake of dopamine and norepinephrine, leading to sympathomimetic effects such as hypertension, tachycardia, bronchodilation, and agitation.

2.10.3.
Clinical characteristics. Rhabdomyolysis, hypoglycemia, seizures, hypertensive crisis, coma, and trauma are several of the complications that can arise with PCP use.

Ketamine
Ketamine is an anesthetic agent (N-methyl-D-aspartic acid receptor antagonist) that is widely used in veterinary medicine and was first synthesized in 1962. As a drug, it causes mood elevation, visual hallucinations, and derealization. Ketamine use has been mainly associated with urinary tract abnormalities, such as inflammatory cystitis, hematuria, and an obstructive picture with hydronephrosis ( Fig. 1 and Table 1). [101] 2.11.1. Incidence. The highest prevalence of recreational ketamine use-0.9%) was reported at the end of 2019. [76] 2.11.2. Pathophysiology. Most of the ketamine metabolites are excreted in to urine by the kidney, only 1% to 5% is eliminated via fecal excretion. Pathophysiology of urinary tract dysfunction involves [41] 1. Formation of gelatinous material from ketamine metabolites (norketamine in the hepatic microsomal system to hydroxynorketamine) that precipitates in the pelvicalyceal systems and causes obstructive renal failure. 2. Bladder epithelial dysfunction with urinary leak, mast cell activation and neurogenic inflammation. 3. IgE-mediated inflammation and hypersensitivity.

Clinical characteristics.
Case reports have shown development of inflammatory cystitis with low volume bladders (Table1), bilateral hydronephrosis and AKI but kidney biopsy had no intrinsic renal pathology.

Anabolic-androgenic steroids
Anabolic androgenic steroids (AAS) include testosterone and its synthetic derivatives, which have been used illicitly by athletes and individuals who wish to increase muscle mass. These substances have been in use since the 1950s. [3]  The lifetime prevalence of AAS use worldwide is estimated to be 1% to 5%. [102] The prevalence in males is 6.4% compared to 1.6% in females. [89] 3.1.2. Pathophysiology. The pathophysiology of renal injury is not yet well established, [5] but 1. hyperfiltration injury is an important factor in patients with markedly elevated lean body mass. 2. Direct toxic effect of AAS on podocytes. 3. Stimulation of renin-angiotensin-aldosterone system 4. Enhancing endothelin, reactive oxygen species, and inflammatory cytokines (TNF-α, IL-1b and IL-6) production is postulated.

Clinical characteristics.
Nephrotoxicity of AAS is only presented in the case reports presented in Table 1. Kidney biopsy from 10 long-term AAS abusers who presented with elevated creatinine and proteinuria showed FSGS (4 out of 10 had perihilar lesions of FSGS, 3 had collapsing lesions) with 69% podocyte foot process effacement. [101]

Narcotic analgesics
Narcotic analgesics like heroin and non-heroin substances relieve pain, induce euphoria, and create mood changes.

Heroin, non-heroin substances
Indians, Assyrians, and Egyptians began to cultivate opium from opium poppy. It was used only by the upper classes to relax and pass time. The isolation of morphine from opium started in 1804 as a way to alleviate the pain of war veterans at the time of the Civil War. [96] Later, cocaine, heroin and other opiates were synthesized and marketed as nonaddictive alternatives to morphine

Heroin
Heroin is the most widely abused opiate in the United States (US). It is extracted from morphine, which can be injected, inhaled, or smoked. The purity of heroin depends on the presence of other drugs or substances called adulterants (commonly used are sucrose, dextrose, mannitol, lactose, starches, powdered milk, caffeine, lidocaine, procaine, methapyrilene, and strychnine). [76] 3.4.1. Incidence. The first known case of nephropathy, term known as heroin-associated nephropathy (HAN), was seen in the early 1970s in New York. [57] 3.4.2. Pathophysiology. Heroin abuse can lead to AKI [103] 1. due to dehydration, exhaustion, rhabdomyolysis, and urinary retention.  [57] Recently endocarditis associated glomerulonephritis has been increasingly seen in IV heroin users. It is almost always right-sided and is associated with crescents in 50% of the cases, 25%-30% with ANCA.

Non-heroin abuse
T's and Blues syndrome-The tablet form of pentazocine is combined with the antihistamine, tripelennamine, dissolved in water, and injected intravenously. This combination is called "T" and "Blue." [68] Oxymorphone/ OPANA ER-In recent years, there has been an increase in the misuse of adulterated oxymorphone injected by mixing the pill with water. This drug has been associated with thrombotic microangiopathy. A case series by Miller et al reported that 9 of 18 patients who used OPANA-ER have developed thrombotic thrombocytopenic purpura and AKI (Table 1 and Figure 2). [75] 3. 6

. Inhalants
Inhalants provide mind-altering effects. Examples include toluene, paint thinners and various anesthetic gases.

Toluene (Gas sniffing)
Toluene is an aromatic hydrocarbon that has been used in industry as an organic solvent. The "sniffing" of toluene in paint, paint thinners, and glue has been primarily associated with neurological complications, but since the early 1970s, several case reports of severe renal complications have been described, as shown in Table 1.
3.7.1. Incidence. As a recreational drug, toluene is most often inhaled nasally (glue sniffing, huffing) and produces acute neurological effects such as euphoria.

3.7.2.
Pathophysiology. The hallmark of toluene intoxication is type I RTA and muscular weakness duet o hypokalemia (hypokalemic paralysis). Pathophysiology primarily involves 1. inhibition of the generation of a hydrogen-ion gradient in the distal tubules resulting in an inability to excrete hydrogen ions as ammonium leading to type I RTA or distal RTA. 2. Overporduction of hippuric acid by toluene metabolism leading to distal RTA. 3. Increased hydrogen ion back diffusion with increased potassium movement into the tubular lumen leading to potassium wasting. 4. Hypokalemic paralysis due to an increased ratio between intra-and extracellular potassium concentrations, which alters membrane polarization and function of excitable tissues such as muscle. 5. AKI caused by vomiting, dehydration, tubular injury and rhabdomyolysis. 6. Rhabdomyolysis occurs by either direct toluene muscular injury, prolonged immobility, hypokalemia or hypophosphatemia.

Clinical characteristics.
The initial effects of toluene inhalation are euphoria, excitement, and exhilaration. As high concentrations are reached, visual and auditory hallucinations, confusion, nausea, vomiting, and loss of self-control are seen. In terms of kidney involvement, microscopic hematuria and proteinuria have been found based on the case reports (Fanconi syndrome) in Table 1. Some cases of AKI, severe normal anion gap metabolic acidosis (type I RTA), hypokalemia, and muscle paralysis has also been found. [105] Kannan • Medicine (2022) 101:50 www.md-journal.com

Designer drugs
Bath salts, K2/Spice/synthetic cannabinoids are designer drugs, which are collectively called synthetic legal intoxicating drugs (SLIDs). They gained popularity as they are relatively cheap, are not detected on standard urine drug screens, and can produce a powerful high.

Bath salts
Bath salts are beta-ketone amphetamine analogs and are derived from cathinone from the "Khat" plant (Catha edulis). [104] These drugs are sold as white-or tan-colored crystalline powders and contain mephedrone and 3,4-methylenedioxypyrovalerone (MDPV). [106] 3.9.1. Incidence. In 2011, "bath salt" use was related to over 20,000 emergency department visits in the US based on a report by SAMHSA. [1] 3.9.2. Pathophysiology. Pathophysiology of renal toxicity of bath salts involves [69] 1. Inhibition of monoamine reuptake (dopamine, norepinephrine) that results in hyperthermia and rhabdomyolysis. 2. Serotonin syndrome. 3. Direct drug effects 4. Norepinephrine and dopamine-induced vasoconstriction (renal ischemia) 3.9.3. Clinical characteristics. Bath salt preparations are pharmacologically similar to amphetamines, which can cause sympathomimetic features like anxiety, agitation, and palpitations. The renal manifestations of bath salts include mild rhabdomyolysis and hyperuricemia. In severe cases, multiorgan failure with anuric AKI that requires continuous renal replacement therapy has been known to occur K2/.

Spice/synthetic cannabinoids
Synthetic cannabinoids have cannabis-or marijuana-like effect. It was initially produced in the laboratories for research purposes but has become popular as "Spice" or "K2." The main categories of synthetic cannabinoids include classic cannabinoids (with a dibenzopyran ring), nonclassic cannabinoids (cycloheylphenols), naphthylmethylindoles, naphthopyrroles, naphthylmethylindenes, naphthylindoles, phenylacetylindoles, methanandamine and other synthetic analogues of endogenous eicosanoids. [10] 3.10.1. Incidence. Among people aged 12 or older, the percentage who were past year marijuana users increased from 11.0 percent (or 25.8 million people) in 2002 to 17.5 percent (or 48.2 million people) in 2019. [1] 3.10.2. Pathophysiology. The exact mechanism of nephrotoxicity of synthetic cannabinoids is not exactly known, but several reports have documented [78] 1. Calcium oxalate crystal deposition in kidney biopsy samples as synthetic cannabinoids is ingested with plants which may have oxalogenic potential. 2. Cannabinoid hyperemesis syndrome resulting in extreme hypovolemia and dehydration leading to AKI. [107] 3. Derangements in the kidney endocannabinoid system (low-level expression of the kidneys (low level expression of CB1 and CB2 receptors in renal podocytes, endothelial cells, mesangial cells and proximal tubules). [108] 4. Potential adulteration with noncannabinoid nephrotoxic contaminants.

Clinical characteristics.
The first report of acute kidney injury (AKI) in patients with use of synthetic cannabinoids was in 2012 in Wyoming. Further investigation led to identification of 16 additional cases of AKI in six different states. Toxicological analysis identified a fluorinated synthetic cannabinoid. Kidney biopsy in these patients revealed acute interstitial nephritis, and acute tubular injury. [109]

Conclusion
Based on this review, there is still a paucity of data in the literature due to under-reporting of cases, inherent problems in finding causal association between a particular drug and the development of a single renal disease, as in most cases, they do not exist as a specific or separate entity, and there is concomitant use of several drugs (with or without adulterants and potentiating factors) at the same time. It is also important to note that not all people exposed to different nephrotoxins will develop kidney disease. However, with the ever-growing global burden of use of recreational drugs and their dependence, it is of paramount importance that clinicians and investigators are aware of the harmful renal effects, as timely intervention and community education can slow the burden of the disease. Furthermore, further research into the pathophysiological mechanisms associated with these drugs will provide a deeper understanding of the renal toxicity.